Women are at an increased risk for cognitive decline after natural or surgical menopause due to the permanent loss of ovarian hormones. Hormone replacement therapy, which is typically prescribed for climacteric symptoms associated with menopause, can also provide some cognitive benefits. However, the adverse side effects of long-term treatment prevent its prolonged use. Few investigations to date have looked at the long-term impact of hormone replacement after treatment has been discontinued. We have developed a middle-aged rodent model of short-term estrogen replacement therapy which is as effective as long-term, continuous treatment at improving spatial working memory. It also induces sustained upregulation of its cognate alpha- receptor, in the hippocampus, a region of the brain required for spatial working memory. While hippocampal function can benefit from estrogen treatment, other cognitive domains may be adversely affected or remain unaffected. Thus, we propose to examine the utility of our model in protecting prefrontal cortical function, which is particularly susceptible to deterioration during advanced aging and can be unaffected or worse, impaired, by prolonged estrogen exposure. Given that estrogen therapy can have opposing effects in a brain region-specific manner and the risks associated with extended use, it is imperative that we develop adjuvant or alternative therapeutic strategies. Aerobic exercise is an obvious candidate because it has general health and cognitive benefits, is neuroprotective during aging, and is a cost-free nonpharmacological intervention. Our main objective, therefore, is to demonstrate the capacity for these two therapies to be used in combination to promote healthy aging post menopause. We expect combination therapy to be maximally beneficial for physiological and brain health. Moreover, evaluating the effects of the two strategies on brain plasticity, alone and in combination, will provide valuable insight into the divergence and overlap in their underlying mechanisms of action.